This invention relates to vitamin D compounds useful in treating and/or preventing secondary hyperparathyroidism and/or the symptoms thereof, and more particularly to the use of the vitamin D compound 2-methylene-19-nor-(20S)-1α,25-dihydroxyvitamin D3, otherwise referred to herein as “2MD” in combination with calcimimetics to treat and/or prevent secondary hyperparathyroidism and/or the symptoms thereof in subjects having secondary hyperparathyroidism.
Secondary hyperparathyroidism refers to the excessive secretion of parathyroid hormone (PTH) by the parathyroid glands in response to hypocalcemia (low blood calcium levels). This disorder is especially seen in subjects with chronic renal failure and often is abbreviated as “SHPT” in medical literature.
Renal disease has become an increasingly important health problem in virtually every country in the world including highly developed countries such as the United States. Presently there are about 250,000 subjects in the United States on renal dialysis who have lost almost complete use of their kidneys. There are approximately ten times more subjects who have lost some degree of renal function due to renal disease and are progressing to complete renal failure. Renal failure is evidenced by a decreased glomeruli filtration rate (GFR) from a high value of 110 ml/minute/1.73 m2 to 30 ml/minute/1.73 m2 where dialysis is often initiated, and may be referred to as Stage 5, Chronic Kidney Disease (CKD).
Many factors contribute to the development of renal disease. High blood pressure is one of the significant contributors, as is having Type I or Type II diabetes. Current treatments for renal failure are limited to hemodialysis, an extremely expensive procedure that currently is supported by federal governments because individuals typically cannot afford this procedure on their own. The annual cost of renal disease in the United States alone is over $42 billion. Accordingly, effective methods for preventing renal disease and treating symptoms thereof would not only provide a major health benefit but would also provide a major economic benefit.
Secondary hyperparathyroidism (SHPT) has been successfully managed with the use of two types of agents: active vitamin D analogs (AVDs) alone or with the addition of a calcimimetic (CM). Regarding vitamin D's role in managing SHPT, it is now universally accepted that vitamin D must first be 25-hydroxylated in the liver and subsequently 1α-hydroxylated in the kidney before it can be converted to its active form, namely 1α,25-(OH)2D3 or “calcitriol.” (See DeLuca, “Vitamin D: The vitamin and the hormone,” Fed. Proc. 33, 2211-2219, 1974; and DeLuca & Schnoes, “Vitamin D: Recent advances,” Ann. Rev. Biochem. 52, 411-439, 1983). Calcitriol then stimulates a number of physiological processes including: stimulating the intestine to absorb calcium, stimulating the kidney to reabsorb calcium, stimulating the intestine to absorb phosphate, and stimulating bone to mobilize calcium when signaled by high parathyroid hormone (PTH) levels. These actions result in a rise in plasma calcium and phosphorus levels that bring about the healing of bone lesions such as rickets and osteomalacia and prevent the neurological disorder of hypocalcemic tetany.
Accordingly, SHPT is a universal complication in subjects with chronic renal failure because subjects with chronic renal failure are unable to convert 25-hydroxy-vitamin D3 from the liver to its active form of 1α,25-(OH)2D3 via 1α-hydroxylation in the kidney. As a result of low levels of circulating 1α,25-(OH)2D3 in subjects with chronic renal failure, intestinal calcium absorption is minimal which subsequently results in insufficient serum calcium levels. In addition, during chronic renal failure, the failing kidneys do not adequately excrete phosphate. When this happens, insoluble calcium phosphate forms in the body and removes calcium from circulation. Ultimately, low levels of circulating 1α,25-(OH)2D3 and inadequate phosphate excretion contribute to hypocalcemia and secondary hyperparathyroidism because when the parathyroid glands sense a low level of serum calcium (i.e., hypocalcemia), the parathyroid glands secrete an elevated amount of PTH in order to raise calcium mobilization from bone to raise serum calcium.
In addition to SHPT resulting from renal failure, SHPT also can result from gastrointestinal malabsorption syndromes (e.g., chronic pancreatitis, small bowel disease, and malabsorption-dependent bariatric surgery in which the intestines do not absorb vitamins and minerals properly), where these syndromes are characterized by insufficient absorption of the fat soluble vitamin D resulting in low levels of circulating 1α,25-(OH)2D3. Other less common causes of secondary hyperparathyroidism are long-term lithium therapy, vitamin D deficiency, malnutrition, vitamin D-resistant rickets, or hypermagnesemia (i.e., abnormally high blood magnesium levels).
As such, overt symptoms of SHPT include increased secretion of PTH. Left unchecked, the elevated secretion of PTH observed in SHPT will lead to the development of renal osteodystrophy. High PTH levels can also lead to: 1) weakening of the bones; 2) calciphylaxis (when calcium forms clumps in the skin and lead to ulcers and potentially death of surrounding tissue); 3) cardiovascular complications; 4) abnormal fat and sugar metabolism; 5) itching (pruritis); and 6) low blood counts (anemia). Less overt symptoms of SHPT include bone and joint pain, bone deformities, broken bones (fractures), swollen joints, kidney stones, increased urination, muscle weakness and pain, nausea, loss of appetite, upper abdominal pain, fatigue, and depression.
Because SHPT results from low levels of circulating calcitriol, calcitriol has been administered as a therapeutic in order to supplement the low levels of circulating calcitriol in subjects with SHPT. In the treatment of SHPT, it is well known that calcitriol binds to the vitamin D receptor (VDR) located in the parathyroid glands to suppress both growth and proliferation of the parathyroid cells and expression of the preproparathyoid gene. (See Demay et al., “Sequences in the human parathyroid hormone gene that bind the 1,25-dihydroxyvitamin D3 receptor and mediate transcriptional repression in response to 1,25-hydroxyvitamin D3.” Proc. Natl. Acad. Sci. USA 89, 8097-8101, 1992; and Darwish & DeLuca, “Identification of a transcription factor that binds to the promoter region of the human parathyroid hormone gene,” Arch. Biochem. Biophys. 365, 123-130, 1999). Because of its ability to suppress parathyroid hormone (PTH), calcitriol has been used with success in the treatment of secondary hyperparathyroidism. (See Slatopolsky et al., “Marked Suppression of Secondary Hyperparathyroidism by Intravenous Administration of 1,25-dihydroxycholecalciferol in Uremic Subjects,” J. Clin. Invest. 74:2136-2143, 1984). However, the use of calcitriol in the treatment of SHPT is not without its drawbacks because calcitriol may cause hypercalcemia resulting from calcitriol's potent action on intestinal calcium absorption and bone mineral calcium mobilization.
As such, less calcemic analogs of calcitriol that exhibit diminished activity on intestinal calcium absorption and/or bone mineral calcium mobilization have been developed and have been found to be nearly as effective as calcitriol in suppressing PTH secretion by cultured bovine parathyroid cells. These include 22-oxacalcitriol (OCT), (Brown et al., “The Non-Calcemic Analog of Vitamin D, 22-oxacalcitriol (OCT) Suppresses Parathyroid Hormone Synthesis and Secretion,” J. Clin. Invest. 84:728-732, 1989), as well as 1,25-(OH)2-16-ene-23-yne-D3, 1,25-(OH)2-24-dihomo-D3, and 1,25-(OH)2-24-trihomo-22-ene-D3. 22-oxacalcitriol has been examined in detail for this action in vivo. (See Brown et al., “Selective Vitamin D Analogs and their Therapeutic Applications,” Sem. Nephrol 14:156-174, 1994, reporting that 22-oxacalcitriol, despite its rapid clearance in vivo, could suppress PTH mRNA). Low, submaximal doses of calcitriol and OCT exhibited comparable inhibition. OCT also has been shown to suppress serum PTH in uremic rats and dogs.
Another analog of calcitriol with low calcemic and phosphatemic action is 19-nor-1,25-(OH)2D2, which is also known as paricalcitol or 19-nor-1α,25-dihydroxy-ergocalciferol. Paricalcitol injection is available commercially as Zemplar® from Abbott Laboratories, Abbott Park, Ill. A paricalcitol (Zemplar®) injection is described in U.S. Pat. No. 6,136,799 and has been approved by the FDA and is marketed for the prevention and treatment of secondary hyperparathyroidism associated with chronic renal failure (CKD Stage 5 or end-stage renal disease (ESRD), GFR<15 mL/min/1.73 m2).
A newer class of drug used to treat SHPT are the so-called “calcimimetics,” one of which is commercially available as Sensipar® (cinacalcet) in the United States and Australia, and as Mimpara® in the European Union. A calcimimetic (CM) is a drug that mimics the action of calcium on the parathyroid gland by allosteric activation of the calcium-sensing receptor that is expressed in the parathyroid gland. In particular, CMs increase the sensitivity of calcium-sensing receptors in the parathyroid gland and trick the parathyroid gland into thinking that there is a sufficient level of serum calcium. As a result of the receptor thinking that there is sufficient serum calcium, PTH secretion is reduced. (See Miller et al., Nephrol Dial. Transplant (2012) 27:2198-2205; Walter et al., BMC Nephrology 2014, 15:81; Wu-Wong et al., Physiological Reports ISSN 2051-817x, pages 1-10; Kumar et al., Drug Metabolism and Disposition, Vol. 21, No. 21, 1491-1500; and Walter et al., J. Pharmacology and Experimental Therapeutics, 2013, 346:229-240). Calcimimetics have achieved positive responses and are FDA approved for use in subjects on dialysis, but have not been approved for use in chronic kidney disease pre-dialysis because, among other concerns, CMs also can increase phosphorus levels. Further, CMs cause hypocalcemia and are provided together with a vitamin D analog (AVD) to both prevent hypocalcemia and to help in suppression of serum PTH. (See Finch et al., Am J. Physiol Renal Physiol 298:F1315-F1322; De Schutter et al., Calcif Tissue Int (2012) 91:307-315; and Jung et al., J. Hypertension, Vol. 30, No. 11, November 2012, 2182-2191). Often CMs are employed when an AVD by itself is unable to suppress the PTH without also causing hypercalcemia. Thus, both a CM and an AVD may be administered to treat SHPT in some subjects.
Thus, therapies that can suppress PTH with minor effects on calcium and phosphate metabolism would be an ideal tool for the control and treatment of secondary hyperparathyroidism. Here, a combination therapy for treating SHPT using a highly potent active vitamin D analog (AVD), namely, 2-methylene-19-nor-(20S)-1α,25-dihydroxyvitamin D3, referred to herein as “2MD” together with a calcimimetic is proposed to suppress serum PTH while maintaining serum calcium in the normal range. (See also U.S. Published Application No. 2014/0005152, the content of which is incorporated herein by reference in its entirety). As such, 2MD together with calcimimetics (CMs) may be useful for treating SHPT in subjects. Here, it is proposed that by administering a combination therapy of 2MD and a CM, a lower dose of 2MD and/or a lower dose of CM may be administered in order to treat SHPT, than the doses that are administered when 2MD and/or the CM are administered alone to treat SHPT. As such, synergy may be observed in the disclosed combination therapy for SHPT using 2MD and a CM. In addition, the disclosed combination therapy may be utilized to avoid the undesirable side effects associated with administering a higher dose of 2MD (e.g., hypercalcemia) and/or the undesirable side effects associated with administering a higher dose of a CM (e.g., hypocalcemia, overly low serum parathyroid hormone levels, nausea, and vomiting) than the lower doses administered in the disclosed combination therapy.